Low-cost, disposable, electrochemical electrode assemblies have special utility as part of infusion fluid delivery systems commonly used in hospital patient care. Such systems infuse nutrients, medications, and the like directly into the patient at a controlled rate and in precise quantities for maximum effectiveness. Infusion fluid delivery systems are connected to a patient at an intravenous (IV) port, in which a hollow needle/catheter combination is inserted into a blood vessel of the patient and thereafter an infusion fluid is introduced into the vessel at a controlled rate, typically using a peristaltic pump. Blood chemistry monitoring systems that are combined with infusion delivery systems of this kind use the IV port to periodically withdraw a blood sample, perform measurements of blood ion concentrations and the like, and then discard the blood or reinfuse it into the patient. The system then resumes delivery of the infusion fluid.
Such combined infusion fluid delivery and blood chemistry monitoring systems include an infusion line and catheter through which the infusion fluid is provided to the patient and blood samples are withdrawn. The infusion line incorporates an electrode assembly having electrochemical sensors that are periodically exposed to the blood samples and thereby provide electrical signals to an analyzer for conversion into corresponding blood chemistry data. A control unit periodically halts delivery of the infusion fluid for a brief interval, during which time a blood sample is withdrawn from the patient into the infusion line and routed to the electrode assembly, which then generates the electrical signals. After the electrical signals have been received by the analyzer, the control unit disposes of the blood or reinfuses the blood sample into the patient, and the flow of infusion fluid is resumed.
The electrode assembly typically, among other types of electrochemical sensors, includes a reference electrode and a plurality of sensing electrodes (sensors) that are each sensitive to a particular ion or species of interest. All of the electrodes are typically embedded in the base of the electrode assembly. For example, ion-sensitive electrodes (ISE) generate electrical signals only in response to contact with the particular ion to which they are sensitive, and therefore provide selective measurement of the amount of that ion in the blood. This type of sensing electrode can be provided to measure, for example, blood calcium, hydrogen ion, chloride, potassium, and sodium. In a differential measurement system, the reference electrode might be another ion-selective electrode (e.g., a chloride or sodium electrode) that is continuously exposed to a calibration or reference fluid. Alternatively, in a non-differential measurement system, a conventional reference electrode (which maintains a fixed potential when exposed either to reference fluid or to analyte) is required.
In a differential measurement system, during the delivery of calibration fluid, the calibration fluid flows past both the reference electrode and the sensing electrodes, and the electrical potential between the reference electrode and each sensing electrode is measured. This provides a calibration measurement of the electrode assembly. During a subsequent blood chemistry measurement, a blood sample is drawn into the electrode assembly, where it comes into contact with the sensing electrodes, but not the reference electrode. The electrical potential between the reference electrode and each sensing electrode is measured again and compared with the earlier calibration measurement to provide an indication of the ion concentration in the blood of the particular ion to which the sensing electrode is sensitive. After measurement is completed, the blood sample is discarded or reinfused from the electrode assembly back into the patient, and delivery of infusion fluid is resumed.
Presently employed electrochemical sensors for clinical diagnostic applications can be divided into three categories: potentiometric, amperometric and ac impedance. For example, hematocrit (Hct), which is defined as the volume percent of red cells in the blood, can be determined by measuring the ac impedance of the blood with a pair of metal electrodes, typically at 1 kilohertz (kHz).
An amperometric sensor correlates the concentration of a specific component of interest to a current output. Typically, oxygen partial pressure (pO.sub.2) and glucose (Glu) are determined with amperometric sensors. An oxygen sensor assembly usually consists of a noble metal (e.g., platinum or gold) working electrode and a suitable counter electrode (e.g., silver/silver chloride). An oxygen permeable, but liquid impermeable, membrane is usually mounted over the sensor assembly to separate the sample from the internal electrolyte to avoid contamination. The sensor measures the limiting current of oxygen reduction at the working electrode according to the following equation: EQU O.sub.2 +2H.sub.2 O+4e.fwdarw.4OH.sup.-
This is accomplished by applying a bias voltage of approximately 700 mV between the working (negative) electrode and the counter (positive) electrode. This is also known as a Clark electrode. The current passing between these two electrodes is proportional to the pO.sub.2 level in the sample.
The glucose sensor is very similar in construction to an oxygen sensor. The difference is that a hydrophilic membrane with immobilized glucose oxidase is used instead of the hydrophobic oxygen membrane. In the presence of glucose oxidase (GOD), the following reaction takes place: EQU Glucose+O.sub.2 .fwdarw.Gluconic Acid+H.sub.2 O.sub.2
In this case, glucose concentration can be determined by either polarizing the working electrode anodically or cathodically by approximately 700 mV to measure the rate of hydrogen peroxide oxidation or oxygen reduction, respectively.
A potentiometric sensor provides a voltage change which is related to the species of interest. Ionic species, such as hydrogen ion (H.sup.+), sodium (Na.sup.+), potassium (K.sup.+), ionized calcium (Ca.sup.++) and chloride (Cl.sup.-), are commonly measured by ion selective electrodes (ISE), a typical class of potentiometric sensors. The commonly used CO.sub.2 sensor, better known as the Severinghaus electrode, is also a potentiometric sensor (and is, in fact, essentially a modified pH sensor). Typically, it consists of a pH electrode and a reference electrode with both covered by a hydrophobic (gas permeable-liquid impermeable) membrane such as silicone. There is a thin layer of weakly buffered internal electrolyte (e.g., 0.001M NaHCO.sub.3) between the hydrophobic membrane and the pH sensing membrane. Carbon dioxide in the sample eventually reaches equilibrium with the internal electrolyte and produces a pH shift as a result of the following equation: EQU CO.sub.2 +H.sub.2 O.fwdarw.H.sup.+ +HCO.sub.3.sup.-
The resulting pH shift is then measured by the pH electrode. Therefore, there is a direct relationship between the CO.sub.2 partial pressure (pCO.sub.2) in a sample and the pH thereof.
The accuracy of measurement obtained with any of the above-described sensors can be adversely affected by drift, particularly after exposure to biological fluids such as whole blood. Therefore, frequent calibration is required. This is particularly true for gases such as pO.sub.2 and pCO.sub.2 because any change in the gas transport properties of the membrane may affect the sensor output. To this end, a number of calibration fluids are usually needed. This is because at least two different calibrant concentration levels are usually required to characterize a sensor. For a multi-parameter system, it is sometimes not possible to use the same two solutions to calibrate all sensors due to concerns such as chemical incompatibility and long term stability. Moreover, since it is technically very difficult to maintain pCO.sub.2 and pO.sub.2 constant at desired calibration levels, most conventional blood chemistry analyzers carry two gas cylinders and several bottles of reagents just to fulfill the calibration requirements. This makes the system bulky and cumbersome to use.
An attempt was made to fill pre-tonometered liquid calibrants sealed into aluminum foil pouches under partial vacuum as calibrants, as described by Burleigh (U.S. Pat. No. 4,734,184). This approach substantially reduced the size, and improved the portability of blood chemistry analyzers. However, the contents of the pouch have a limited life once the pouch is opened.
The current trend is to move away from bench top analyzers towards the use of bedside analytical systems. Moreover, instead of taking samples from the patients, sensors are either miniaturized and inserted into a blood vessel (in vivo) or constructed as part of a flow cell connected to the patient end of an existing vascular access port (ex vivo) to provide continuous monitoring of blood chemistry.
The in vivo approach is conceptually more attractive because it provides continuous results without intervention. However, it is much more difficult to implement in practice. The major hurdle is, of course, the blood clotting problem. Blood compatibility has always been a challenging issue. Even with a short term solution in hand, once sensors are placed in the blood stream, repeated calibration becomes very difficult.
The ex vivo approach, originally described by Parker (U.S. Pat. No. 4,573,968), employs a control unit to periodically withdraw a small amount of blood to come in contact with sensors (which are incorporated into an in-line flow cell) when a reading is desired. After a measurement is taken, the control unit resumes delivering physiological saline into the blood vessel. As a result, the blood drawn is effectively flushed back into the patient and the sensors are washed clean. Kater (in U.S. Pat. No. 4,535,786) discloses a method to use an infusible intravenous (I.V.) saline solution to calibrate ionic species in the biological fluid. However, Kater does not address the calibration of species such as glucose, pO.sub.2, and pCO.sub.2, as contemplated by the present invention.
As previously indicated, all blood chemistry sensors require frequent calibration in order to maintain the accuracy of measurement. In a multi-parameter bench top analyzer system, it often requires more than one calibration fluid (and/or gas) to accomplish this task. In an ex vivo blood chemistry monitor, it is much more desirable to use a single calibration solution for all the sensors, and to flush the sensors clean. In a multi-parameter ex vivo system, such as the VIA 1-01 Blood Chemistry Monitor (available from Via Medical Corporation, San Diego, Calif.), i.e., a system that measures one or more of Na.sup.+, K.sup.+, Ca.sup.++, Mg.sup.++, pH, pCO.sub.2, pO.sub.2, glucose, lactate and hematocrit, this requirement becomes very demanding.
In particular, the calibration of pH and pCO.sub.2 remains a challenge. In an aqueous solution, these two parameters are inter-related by the following equation: EQU CO.sub.2 +H.sub.2 O.fwdarw.H.sup.+ +HCO.sub.3.sup.-
At 37.degree. C., the pH in a simple bicarbonate-containing solution is equal to EQU 6.10+log {[HCO.sub.3.sup.- ]/0.0301 pCO.sub.2 }
Since the normal pCO.sub.2 in arterial blood is approximately 40 mmHg, while the atmosphere contains 0.2-0.5 mmHg of CO.sub.2, atmospheric CO.sub.2 levels are not only too low, but they are also too variable to serve as a calibration point. Hence, an external CO.sub.2 source is required. Normally, the approach used in the art is to tonometer the solution with a known CO.sub.2 -containing gas, and then package the gas-equilibrated solution in a sealed container. This is not only costly but also requires considerable effort to demonstrate its safety as an infusible solution.
Although U.S. Pat. No. 4,736,748 (Nakamura) suggests that simultaneous calibration for Na.sup.+, K.sup.+, Ca.sup.++, glucose and hematocrit, can be carried out with Ringer's Lactate having glucose added thereto, such a solution could not possibly be used for pH, pCO.sub.2 and/or pO.sub.2 calibration because the solution has no well defined pH value or pO.sub.2 value, and contains essentially no CO.sub.2. Indeed, since the amount of oxygen dissolved in Lactated Ringer's solution is not fixed (being a function of ambient temperature and barometric pressure--parameters which Nakamura does not contemplate monitoring), the reference does not teach how to use Lactated Ringer's solution as an oxygen calibrant. Moreover, the oxygen partial pressure in physiological saline is substantially higher than that in blood. It would be desirable for a calibration solution to have oxygen levels which are relatively close to physiological levels, regardless of what type of sensor is employed. Furthermore, Nakamura does not address measurement of hematocrit levels at all.
While Burleigh, supra., describes a solution which can be used for calibration of CO.sub.2, the reference does not contemplate the use of an infusible calibrant, much less a substantially non-buffered, infusible calibrant. Indeed, the Burleigh CO.sub.2 calibration solution would not be acceptable for infusion. In contrast to the practice of the present invention, after sample analysis, Burleigh directs assayed fluids into a waste collection reservoir. In accordance with the present invention, a very different analytical system is contemplated wherein sample withdrawn from a subject is reinfused after analysis. Thus, a different calibration solution is required for the practice of the present invention relative to what is taught in the art. Since Burleigh does not contemplate a substantially non-buffered, infusible calibrant, the reference provides no guidance as to suitable calibration solutions for use with combined infusion fluid delivery/blood chemistry measurement systems, as contemplated herein.
Sone et al., U.S. Pat. No. 5,132,000 (1992) is similar to Burleigh in that the reference describes solutions which can be used for calibration of CO.sub.2 -containing solutions. The reference does not, however, contemplate the use of an infusible calibrant. Similar to Burleigh, the Sone calibration solutions would not be acceptable for infusion. Successful analysis according to the Sone teaching requires the use of strong pH buffering. The level of buffering and ionic strength required by Sone clearly makes such solutions unacceptable for infusion.
From the discussion above, it should be apparent that there is a need for calibration solutions useful, for example, in combined infusion fluid delivery and blood chemistry measurement systems that allow accurate, reliable measurements of blood chemistry, that avoid the need for multiple calibration and/or reference solutions, and that are relatively easy to prepare by mixing injectable media that are readily available for patient use as "off-the-shelf" items. The present invention satisfies these needs.